Bioswellable sutures

ABSTRACT

Bioswellable sutures are provided in the form of absorbable, compliant monofilaments of an amphiphilic copolyester, an absorbable multifilament braid, a non-absorbable monofilament with swellable outer layer, a non-absorbable multifilament braid with an absorbable monofilament core of an amphiphilic copolymer, and a non-absorbable, multifilament braid molecularly integrated with an outer sheath that is highly hydrophilic.

FIELD OF THE INVENTION

This invention relates to bioswellable surgical sutures that undergoswelling when placed in the biological environment, resulting in anincrease in their cross-sectional area of at least 20 percent.Clinically, the bioswellable sutures minimize the traditional disparitybetween the needle and suture cross-sectional areas and subsequently,reduce the needle-hole leakage and associated blood loss, delay inhemostasis, and risk of infection. The bioswellable sutures, asdescribed in this invention, are presented as preferred or superioralternatives to those commonly used in surgery, and specifically, in thecase of colorectal, cardiovascular, laparoscopic, and microsurgicalprocedures.

BACKGROUND OF THE INVENTION

Most mechanical ligations of living tissues using surgical suturesrequire a combination of a thread and needle. In most cases, the needlediameter far exceeds that of the suture and the needle-to-suturediameter can be as high as 2:1 or 3:1. This can result in leakage ofbodily fluids, including blood, through needle-created holes aboutimplanted suture thread. Depending on the surgical site, this can leadto bleeding and infection. A few attempts have been made in earlierdecades to minimize needle hole leakage without achieving a clinicallyoptimum solution.

In a study by C. M. Miller and coworkers [Surgery, 10(2), 156 (1987)] onreduced anastomotic bleeding and reduction of blood loss from a vascularanastomosis when one is using an expanded polytetrafluoroethylene(ePTFE) graft, two sutures were used, one made of ePTFE and the other ofpolypropylene, which were designed to have a needle-to-suture diameterratio of about 1:1. Theoretically, this allows the suture to completelyfill the graft needle hole and control bleeding. These sutures wereevaluated in a heparin-treated, canine in vivo model to measure graftneedle-hole bleeding. Results of the study, along with subjectiveevaluations of the sutures' handling qualities led to the conclusionthat sutures produced with needle-to-suture ratios of 1:1 greatly reducegraft needle-hole bleeding and will be a useful addition to the vascularsurgeon's armamentarium.

In an approach to prevent needle-hole bleeding during vascularanastomosis using expanded polytetrafluoroethylene (ePTFE) graftstreated with sealants, investigators of the prior art noted that FibrinGlue (FG) is more effective than a thrombin-soaked gelatin sponge forachieving hemostasis of needle- or suture-hole bleeding. However, therisk of infection associated with these naturally derived sealants wasnot ruled out.

Fibrin glue is frequently used to seal and cover the anastomoses in manyoperations. However, in the case of gastrointestinal surgeries, theanastomoses are potentially contaminated and FG may promote bacterialgrowth, thus increasing the risk of leakage

The above-noted accounts of the prior art dealing with differentapproaches to minimize suture- or needle-hole bleeding or leakage andassociated undesirable outcomes illustrate the limited success of theprior art investigators in providing a clinically optimum solution tothis problem. This prompted the pursuit of the present invention whichdeals with the development of a broad range of novel, bioswellable,absorbable and non-absorbable sutures, which can be used moreeffectively in minimizing or eliminating suture- or needle-hole leakageunder the prevailing conditions of several surgical procedures.

SUMMARY OF THE INVENTION

This invention deals, in general, with bioswellable surgical sutureswhich undergo at least 20 percent increase in their cross-sectional areawhen placed in a biological environment. One specific aspect of thisinvention deals with a bioswellable suture comprising a compliantmonofilament comprising an absorbable polyether-ester, the monofilamenthaving a tensile modulus of less than about 400 Kpsi and exhibiting anat least 20 percent increase in cross-sectional area and an at least 5percent decrease in tensile modulus when placed in a biologicalenvironment, wherein the polyether-ester comprises a polyether glycolend-grafted with at least one cyclic monomer selected from the groupconsisting of l-lactide, glycolide, p-dioxanone, trimethylene carbonate,ε-caprolactone, 1,5-dioxepan-2-one and a morpholinedione, and whereinthe polyether glycol is selected from the group consisting ofpolyethylene glycol, polypropylene glycol, and block copolymers ofethylene glycol and propylene glycol. Preferably, the polyether glycolis a solid polyethylene glycol having a molecular weight of greater thanabout 8 kDa and more preferably, the polyethylene glycol comprises atleast about 10 weight percent of the total polyether-ester mass. It isalso preferred that the bioswellable suture further comprising a surfacecoating on the monofilament, wherein the surface coating comprises atleast about 0.01 weight percent of total mass of the suture, wherein thesurface coating comprises an ε-caprolactone copolymer. Preferably, thesurface coating contains at least one bioactive agent selected from thegroup consisting of antimicrobial agents, anti-inflammatory agents, andantineoplastic agents, the coated monofilament being capable ofretaining at least about 40 percent of its initial breaking strengthafter placing in the biological environment for four days.

Another specific aspect of this invention deals with a bioswellablesuture comprising a compliant monofilament comprising a core layer andan outer layer molecularly integrated with the core layer, the outerlayer comprising highly hydrophilic moieties derived from grafts of atleast one unsaturated monomer selected from the group consisting ofhydroxyethyl methacrylate, maleic anhydride, itaconic anhydride, andmethacrylic acid, the monofilament having a tensile modulus of less thanabout 400 Kpsi and exhibiting an at least 20 percent increase incross-sectional area and an at least 5 percent decrease in tensilemodulus when placed in a biological environment, wherein the corecomprising a non-absorbable polymer selected from the group consistingof isotactic polypropylene, an aliphatic polyamide, and a segmentedcopolyester, preferably comprising polytetramethylene terephthalate. Itis also preferred that the outer layer of the aliphatic polyamide corecomprises a polyethylene oxide graft. It is most preferred that theouter layer of the compliant monofilament suture contains at least onebioactive agent selected from the group consisting of anti-inflammatoryagents, antimicrobial agents, and antineoplastic agents.

A key aspect of this invention deals with a bioswellable sutureexhibiting an at least 20 percent increase in cross-sectional area andan at least 5 percent decrease in tensile modulus when placed in abiological environment, wherein the suture comprising a braidednon-absorbable multifilament encased in a molecularly integrated, highlyswellable sheath, comprising a highly hydrophilic moieties derived fromgrafts of at least one monomer selected from the group consisting ofhydroxyethyl methacrylate, maleic anhydride, itaconic anhydride, andmethacrylic acid, itaconic anhydride.

Another key aspect of this invention deals with a bioswellable suturecomprising an absorbable monofilament core and a non-absorbablemultifilament braided sheath, the core comprising polyethylene glycolend-grafted with at least one monomer selected from the group consistingof l-lactide, glycolide, trimethylene carbonate, p-dioxanone,1,5-dioxepan-2-one, ε-caprolactone, and a morpholinedione, the sheathcomprising a heterochain polymer selected from the group consisting ofNylon 6, Nylon 66, polyethylene terephthalate, polybutyleneterephthalate, polytrimethylene terephthalate, segmented copolymers ofpolyalkylene terephthalate and polytetramethylene glycol, wherein thebioswellable suture further comprising a surface coating comprising aε-caprolactone/glycolide copolymer or a polyethylene glycol end-graftedwith a mixture of ε-caprolactone and glycolide.

A special aspect of this invention deals with a bioswellable braidedmultifilament suture comprising an absorbable polyether-ester, theindividual filaments exhibiting at least 5% increase in cross-sectionalarea when placed in the biological environment, wherein thepolyether-ester comprises a polyether glycol end-grafted with at leastone cyclic monomer selected from the group consisting of l-lactide,glycolide, p-dioxanone, trimethylene carbonate, ε-caprolactone,1,5-dioxepan-2-one and a morpholinedione, and wherein the suture furthercomprises a surface coating comprising an ε-caprolactone copolymer.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

This invention deals with a broad range of new, absorbable andnon-absorbable, compliant, bioswellable sutures that are designed tosatisfy unmet clinical requirements associated with (1) minimizing oreliminating suture- or needle-hole bleeding and blood loss in surgicalprocedures involving highly vascularized tissues and particularly, inthe case of vascular anastomosis where low tear strength and/ormicroporous synthetic vascular grafts or patches are used; and (2)minimizing or eliminating suture- or needle-hole leakage and risk ofinfection encountered during gastrointestinal and colorectal surgeries.The bioswellable sutures, subject of this invention, can be presented aspreferred alternatives to more conventional sutures and particularly,those used in the area of (1) ophthalmic and/or plastic surgery; (2)laparoscopic surgery, and (3) tissue engineering.

The bioswellable sutures can be in the form of (1) an absorbable,compliant monofilament comprising an amphiphilic copolyester; (2) anon-absorbable monofilament with swellable outer layer; (3) anon-absorbable multifilament braid with an absorbable monofilament corecomprising an amphiphilic copolymer; and (4) a non-absorbable,multifilament braid molecularly integrated with an outer sheath that ishighly hydrophilic.

An important general aspect of this invention deals with two types ofabsorbable, bioswellable monofilament sutures having fast- andslow-absorption and breaking strength retention (BSR) profiles, not onlyas novel sutures for new applications, but also as preferredalternatives to several commercial sutures, including the only twoavailable ones which were developed, specifically, to address thesuture- or needle-hole bleeding. Clinical attributes of thebioswellable, absorbable monofilament sutures, subject of thisinvention, are discussed in the following paragraphs and theiradvantages over competitive commercially available sutures are alsonoted.

In a review by P. Hogston [The Obstetrician & Gyneacologist, 3(3), 127(2001)] on suture choice in general gynecological surgery, the authoranalyzed many of the issues that need further attention toward improvingthe performance and clinical efficacy of surgical sutures whileminimizing or eliminating a number of undesirable outcomes. Issuespertinent to the present invention are those dealing with (1) the factthat as of 1990, 66 percent of the surgeons used catgut sutures and only33 percent used synthetic sutures in the closure of the vaginal vault athysterectomy, because of catgut suture's relatively fast absorption,ease of handling, and associated knot security—this is in spite of themarginal breaking strength and frequently acknowledged high tissuereaction encountered with catgut sutures compared with their syntheticcounterparts; (2) preferred use of synthetic, absorbable sutures withdelayed absorption profile in incontinence surgery—these sutures werepreferred over the easier-to-handle catgut because of their delayedabsorption; (3) the fact that as of 1990, rapidly absorbable sutureswere widely used in prolapse surgery, but as many as 30 percent of theoperations were repeat procedures—this and subsequent studies justifiedthe preferred use of synthetic sutures having a delayed absorptionprofile in prolapse surgery; and (4) the limited use of microporouspolytetra-fluoroethylene (ePTFE, Gore-Tex®) as a non-absorbable suturein reconstructive gynecological surgery to decrease suture-linebleeding, in spite of its problematic knot security (at least seventhrows are required) and the risk of infection generally associated withnon-absorbable sutures. Accordingly, there exists a definite need fornew synthetic absorbable sutures having (1) the attributes of catgut interms of ease of handling and knot security, but free of theirundesirable high tissue reactions and marginal breaking strength, foruse in the closure of the vaginal vault at hysterectomy—the proposedhigh strength, amphiphilic, fast absorbing, compliant, bioswellablesutures, which undergo further increase in compliance in the biologicenvironment to provide optimum knot security, are likely to be preferredalternatives to catgut suture in this application; (2) delayedabsorption can be presented as preferred alternatives to catgut andrapidly absorbing polyglycolide sutures for use in incontinence surgery,using a similar rationale to that presented above—the amphiphilic, highstrength, slow-absorbing, compliant, bioswellable sutures, subject ofthis invention, which undergo further increase in compliance in thebiologic environment to provide optimum knot security, are likely tomeet the requirements of the new alternative sutures to both catgut andpolyglycolide sutures; (3) delayed absorption can be used as preferredsubstitutes for rapidly absorbable sutures for use in prolapsesurgery—the proposed amphiphilic, high strength, slow-absorbing,compliant, bioswellable sutures, which undergo further increase incompliance to provide optimum knot security are likely to meet therequirements of such new sutures; (4) delayed absorption and non-porous,surface-coated (with lubricious copolymer) sutures can be presented aspreferred alternatives to Gore-Tex® sutures for use in reconstructivegynecological surgery as they are expected to have improved tie-downcharacteristics, higher knot security, and a much lower risk ofinfection—absorbable sutures are associated with lower risk of infectionthan their non-absorbable counterparts. Collectively, the two types ofbioswellable, absorbable sutures (fast- and slow-absorbing), subject ofthis invention, are expected to present the general gynecologicalsurgeon with preferred alternatives to currently used sutures in theirarea of clinical practice.

Fibrin glue (FG) is frequently used to seal and cover the anastomoses inmany operations. However, in the case of gastrointestinal surgeries, theanastomoses are potentially contaminated and FG may promote bacterialgrowth, thus increasing the risk of leakage. Bioswellable,slow-absorbing sutures and preferably those containing an antimicrobialagent in their coating may prevent leakage through needle/suture holes,which will help in managing potential infection.

Cited in the prior art is a study on reducing the incidence and managingthe consequences of anastomotic leakage after rectal resection, theinvestigators noted that anastomotic dehiscence is a serious,life-threatening complication of any rectal anastomosis and may beassociated with an increased risk of rectal cancer recurrence. In thisrespect, the coated, slow-absorbing, bioswellable sutures, capable ofthe controlled delivery of antimicrobial agents, subject of thisinvention, can be presented as superior alternatives to traditionalsutures. The bioswellable sutures will be capable of preventing needlebleeding and leakage of potential infected intestinal contents whileprophylactically managing infection at the suture line.

Contrasting the bioswellable, absorbable, monofilament sutures, subjectof this invention, with the commercial, non-absorbable sutures known inthe trade as Gore-Tex® and HemoSeal®, as outlined below, justifiesdenoting the absorbable, bioswellable sutures as their preferredalternatives.

Although both the tapered polypropylene suture-needle combination(Hemo-seal®) and expanded polytetrafluoroethylene suture (Gore-Tex®)have been accepted by a number of vascular surgeons, these sutures dosuffer from a number of limitations. These include (1) diminishedbreaking strength at the tapered segment of the Hemo-seal; (2) thecompromised needle pull strength in Hemo-seal; (3) the surface porosityof Gore-Tex, which may harbor microorganisms leading to infection; (4)the poor tie-down characteristics of the Gore-Tex suture; (5) thebreaking strength of an unknotted and knotted ePTFE suture issignificantly less than most clinically accepted sutures; (6) the poorknot security of Gore-Tex® and the need to use at least seven throws;(7) tendency of Gore-Tex® to creep during suturing and lose its abilityto recover its original uncompressed large diameter; (8) poor tearstrength of Gore-Tex® and possible production of delaminated PTFEfragments; and (9) the high number of Gore-Tex throws and high inherentmodulus and stiffness of PTFE as a polymer, can lead to a high degree ofbiomechanical incompatibility, which, in turn, may increase tissuereaction and likelihood of infection.

The swellable, absorbable sutures, subject of this invention aredesigned to help minimize suture line bleeding, and the unique chemicalstructure of their polymers allows the needle attachment to itsmonofilament suture thread, which expands radially, immediately afterapplication, to fill the needle hole. This is expected to reduce bloodloss and shorten time to hemostasis.

Interest of the surgical community as well as patients in minimallyinvasive surgical procedures and subsequent reliance on laparoscopictechniques has grown significantly over the past two decades. A numberof recent applications testifying to this trend have focused on thesuccessful use of laparoscopy in a broad range of areas, including (1)treatment of morbid obesity; (2) surgery for colon cancer; (3) radicalcystectomy with continent urinary diversion; (4) myomectomy forsymptomatic uterine myomas; and (5) surgical management of invasivecervical cancer.

Laparoscopic surgery has developed out of multiple technologyinnovations. In the treatment of morbid obesity, several surgicalprocedures are currently available, including gastric bypass,bilio-pancreatic diversion (BPD) with duodenal switch, and theadjustable gastric band. These operations may be performed usinglaparoscopic surgical techniques to minimize peri-operative morbidityand postoperative recovery time. Good evidence exists for thelaparoscopic approach for colon cancer patients with outcomes comparableto open surgery. Laparoscopic radical cystectomy with urinary diversionhas evolved rapidly throughout the past decade. Short-term data haveshown that this is a feasible technique that respects the basicprinciples of surgical oncology. However, the possibility of decreasedblood loss, improved visualization, shorter hospital stay, and lesspostoperative pain are balanced against technical difficulty, longoperative times, and unproved long-term efficacy compared with the opengold standard. Laparoscopy has been a long-standing technique forgynecologic surgery with increasing shifts toward total laparoscopichysterectomies, myomectomies, and for staging of gynecologic cancers. Aslaparoscopic instrumentation becomes more advanced, there will begreater application in a wide range of procedures traditionallyperformed open. More importantly, historical sutures that are now beingutilized in laparoscopic surgery are done in the absence of comparabledata to verify efficacy. This would apply to the handling of suture withlaparoscopic instruments which can fray monofilament sutures, less thanoptimal knot security in the setting of intra- and extracorporeal knottying, memory and handling issues that may influence insertion throughthe trocars and ability to suture tissue. In short, the inherent loss oftactile capability and handling as compared to open surgery and theparadigm shift toward laparoscopy will inevitably increase the need todevelop suture material which reproduce the handling and knot securitythat have historically been developed for open surgical procedures.

Contrasting the growing significance of laparoscopic surgery with thelimitations associated with presently used sutures in common, openprocedures makes a compelling case to explore the use of bioswellableabsorbable sutures, subject of this invention, because of their manyintegrated attributes. These include (1) their expected ability toprevent needle hole bleeding; (2) having a broad range of tailoredabsorption and strength retention profiles to meet the requirements ofspecific surgical procedures; (3) being compliant and becoming morecompliant in the biological environment; (4) having high breakingstrength, while being easy-to-handle and providing exceptional knotsecurity; and (5) being available in microsurgical sizes.

Interest in plastic surgery and microsurgical procedures has grownsignificantly over the past two decades and is expected to continue at afaster rate in the forthcoming years. For both areas, where absorbablesutures are most useful, suture line bleeding and interfering withhemostasis are major concerns. And limitation associated with the use ofcommon sizes of absorbable monofilament sutures having limited range ofabsorption and strength profile evokes the need to explore the use ofthe bioswellable, absorbable sutures having the unique propertiesoutlined in the previous paragraph. More importantly is the fact thatthe bioswellable sutures can be and have been produced in our laboratoryin sizes corresponding to about 70 micron in diameter. Additionally,these microsutures can undergo swelling in saline at room temperature tomore than 70 percent of their original cross-sectional area.

In his review of articular cartilage injuries of the knee, andspecifically the use of autogenous cartilage implantation as a treatmentoption, A. F. LaPrade and colleagues [Physicians & Sports Medicine, 29,53 (2001)] described the preparation of the patient's own chondrocytesfor implantation at the site of the articular cartilage defect.Implantation of these cells requires an open incision, similar to theincision for a total knee replacement procedure, and arthrotomy. Thearticular cartilage lesion is isolated, and all degenerative cartilagedebrided. Scar tissue is removed from the bed of the defect. The size ofthe articular cartilage defect is then templated, and a matching pieceof periosteum is harvested from the distal femur or the proximal tibia.The free piece of periosteum is microsutured into the edges of thedefect; it is essential to obtain a watertight seal. Then, fibrin glueis placed around the edges of the suture line to further insure thatcells do not leak through the suture holes. The prepared implantationcells are then injected under the periosteal patch. The injection siteis closed with a suture and fibrin glue.

This is a excellent illustration of the importance of minimizing suturehole leakage in the growing area of tissue engineering, which is beyondthe traditional surgical procedure where sutures are routinely used.

This invention deals, in general, with bioswellable surgical sutureswhich undergo at least 20 percent increase in their cross-sectional areawhen placed in a biological environment. One specific aspect of thisinvention deals with a bioswellable suture comprising a compliantmonofilament comprising an absorbable polyether-ester, the monofilamenthaving a tensile modulus of less than about 400 Kpsi and exhibiting anat least 20 percent increase in cross-sectional area and an at least 5percent decrease in tensile modulus when placed in a biologicalenvironment, wherein the polyether-ester comprises a polyether glycolend-grafted with at least one cyclic monomer selected from the groupconsisting of l-lactide, glycolide, p-dioxanone, trimethylene carbonate,ε-caprolactone, 1,5-dioxepan-2-one and a morpholinedione, and whereinthe polyether glycol is selected from the group consisting ofpolyethylene glycol, polypropylene glycol, and block copolymers ofethylene glycol and propylene glycol. Preferably, the polyether glycolis a solid polyethylene glycol having a molecular weight of greater thanabout 8 kDa and more preferably, the polyethylene glycol comprises atleast about 10 weight percent of the total polyether-ester mass. It isalso preferred that the bioswellable suture further comprising a surfacecoating on the monofilament, wherein the surface coating comprises atleast about 0.01 weight percent of total mass of the suture, wherein thesurface coating comprises an ε-caprolactone copolymer. Preferably, thesurface coating contains at least one bioactive agent selected from thegroup consisting of antimicrobial agents, anti-inflammatory agents, andantineoplastic agents, the coated monofilament being capable ofretaining at least about 40 percent of its initial breaking strengthafter placing in the biological environment for four days.

Another specific aspect of this invention deals with a bioswellablesuture comprising a compliant monofilament comprising a core layer andan outer layer molecularly integrated with the core layer, the outerlayer comprising highly hydrophilic moieties derived from grafts of atleast one unsaturated monomer selected from the group consisting ofhydroxyethyl methacrylate, maleic anhydride, itaconic anhydride, andmethacrylic acid, the monofilament having a tensile modulus of less thanabout 400 Kpsi and exhibiting an at least 20 percent increase incross-sectional area and an at least 5 percent decrease in tensilemodulus when placed in a biological environment, wherein the corecomprising a non-absorbable polymer selected from the group consistingof isotactic polypropylene, an aliphatic polyamide, and a segmentedcopolyester, preferably comprising polytetramethylene terephthalate. Itis also preferred that the outer layer of the aliphatic polyamide corecomprises a polyethylene oxide graft. It is most preferred that theouter layer of the compliant monofilament suture contains at least onebioactive agent selected from the group consisting of anti-inflammatoryagents, antimicrobial agents, and antineoplastic agents. A key aspect ofthis invention deals with a bioswellable suture exhibiting an at least20 percent increase in cross-sectional area and an at least 5 percentdecrease in tensile modulus when placed in a biological environment,wherein the suture comprising a braided non-absorbable multifilamentencased in a molecularly integrated, highly swellable sheath, comprisinga highly hydrophilic moieties derived from grafts of at least onemonomer selected from the group consisting of hydroxyethyl methacrylate,maleic anhydride, itaconic anhydride, and methacrylic acid, itaconicanhydride.

Another key aspect of this invention deals with a bioswellable suturecomprising an absorbable monofilament core and a non-absorbablemultifilament braided sheath, the core comprising polyethylene glycolend-grafted with at least one monomer selected from the group consistingof l-lactide, glycolide, trimethylene carbonate, p-dioxanone,1,5-dioxepan-2-one, ε-caprolactone, and a morpholinedione, the sheathcomprising a heterochain polymer selected from the group consisting ofNylon 6, Nylon 66, polyethylene terephthalate, polybutyleneterephthalate, polytrimethylene terephthalate, segmented copolymers ofpolyalkylene terephthalate and polytetramethylene glycol, wherein thebioswellable suture further comprising a surface coating comprising aε-caprolactone/glycolide copolymer or a polyethylene glycol end-graftedwith a mixture of ε-caprolactone and glycolide.

Further illustrations of the present invention are provided by thefollowing examples:

EXAMPLE 1 Two-Step Synthesis of Amphiphilic Polyether-Esters and TheirCharacterization (PI Series): General Methods

The first step of the two-step method entails end-grafting highmolecular polyethylene glycol (PEG) with trimethylene carbonate (TMC) inthe presence of stannous octanoate as the catalyst, at a selectedtemperature range until an almost complete consumption of TMC isachieved. In the second step, one or more cyclic monomer(s) are thenmixed with the TMC-end-grafted PEG. The reaction is continued tocompletion at a selected temperature range. Thirteen typical polymers(PI-F-1 to PI-F-4 and PI-S-1 to PI-S-9) were prepared using this generalprotocol and following the experimental scheme outlined below for theirsynthesis and characterization.

Predried crystalline, PEG-35 (mol. Wt.=35 kDa) was mixed, under nitrogenin a stainless steel reactor equipped for mechanical stirring, with thedesired amount of trimethylene carbonate monomer in the presence ofstannous octanoate as a catalyst. The mixture was heated and stirred toachieve complete dissolution of all reactants. The mixing was continuedwhile heating to a polymerization temperature of 140° C. or 150° C.depending on the composition. The reaction was maintained at thattemperature while stirring until essentially complete monomer conversionwas achieved (˜0.5-1.5 hours depending on the monomer concentration). Acharge of cyclic monomer(s) was then added and the mixture stirred toachieve complete dissolution of all reactants (mixing temperatures of110° C., 140° C. or 150° C. were used depending on the composition). Themixing was continued while heating to a polymerization temperature of160° C., 170° C., or 180° C., depending on the type and concentration ofcyclic monomer(s). The reaction was maintained at that temperature whilestirring until the product became too viscous to stir and essentiallycomplete monomer conversion was achieved (7-12 hours depending on thetype and concentration of cyclic monomer(s)). At this stage,polymerization was discontinued, the product was cooled, isolated,ground, dried, and traces of residual monomer were removed bydistillation under reduced pressure using a temperature that is belowthe copolymer melting temperature (T_(m)), but not exceeding 110° C.

The resulting dry copolymers were characterized for identity andcomposition (IR, NMR), thermal properties, namely T_(m) and ΔH_(f)(DSC), molecular weight in terms of inherent viscosity (solutionviscometry in CHCl₃ or hexafluoroisopropyl alcohol), or number/weightaverage molecular weight (GPC), and melt viscosity (melt rheometer). TheΔH_(f) is used as an indirect measure of percent crystallinity.Pertinent polymerization charge/conditions and analytical data aresummarized in Tables I and II.

TABLE I Synthesis and Properties of Type PI Fast-Absorbing AmphiphilicPolyether-esters (PI-F-1 to PI-F-4) Composition of Charge PEG/TMC/Polyester Polymer PEG M_(n), Polyester, Monomer Types Catalyst DSC DataNumber kDa (wt) & molar ratios^(a) M/C^(b) I.V.^(c) T_(m), ° C. ΔH_(f),J/g PI-F-1 35 20/5/75 80/20 G/CL 6000 1.38 218 72 PI-F-2 35 20/5/7590/10 G/TMC 6000 1.13 — — PI-F-3 35 25/2/73 87/13 G/TMC 6000 — — —PI-F-4 35 25/2/73 75/25 G/CL 6000 1.53 60, 222 22, 52 ^(a)G = Glycolide;CL = ε-caprolactone; TMC = trimethylenecarbonate. ^(b)Molar ratio ofmonomer to stannous octanoate. ^(c)Inherent viscosity in HFIP

TABLE II Synthesis and Properties of Type PI Slow-Absorbing AmphiphilicPolyether-esters (PI-S-1 to PI-S-9) Composition of Charge PEG/TMC/Polyester GPC^(c) Data DSC Data Polymer PEG M_(n), Polyester, MonomerTypes Catalyst Mn, Mw, Tm, ΔH_(f), Number kDa (wt) & molar ratios^(a)M/C^(b) kDa kDa I.V.^(d) ° C. J/g PI-S-1 35 25/15/60 88/12 LL/G 200048.0 82.9 1.16 53, 27, 143 22 PI-S-2 35 28/12/60 95/5 LL/G 4000 44.073.7 1.05 51, 32, 145 31 PI-S-3 35 31/9/60 95/5 LL/G 4000 39.9 64.1 1.0051, 42, 127 15 PI-S-4 35 31/2/67 95/5 LL/G 3000 41.4 69.6 1.01 49, 21,146 27 PI-S-5 35 20/5/75 92/8 LL/G 3000 91.0 128.2 1.23 154 34 PI-S-6 3527/3/70 100 LL 2500 51.9 82.2 0.96 53, 14, 172 34 PI-S-7 35 25/2/73 97/3LL/TMC 1800 56.0 164.8 0.92 160 30 P1-S-8 35 20/2/78 96/4 LL/CL 3000101.4 198.9 1.52 46 3, 177 47 PI-S-9 35 23/2/75 96/4 LL/CL 3000 99.6187.4 1.28 165 33 ^(a)G = Glycolide; LL = l-lactide; TMC = trimethylenecarbonate; CL = ε-caprolactone. ^(b)Molar ratio of monomer to stannousoctanoate. ^(c)Gel permeation chromatography in CH₂Cl₂. ^(d)Inherentviscosity in CHCl₃

EXAMPLE 2

One-Step Synthesis of Amphiphilic Polyether-Esters and TheirCharacterization (PII Series): General Method

The copolymers were prepared using a one-step scheme. This entaileddirect end-grafting of high molecular weight PEG with one or moremonomer(s). the reaction conditions were similar to those used in thesecond-step of the two-step scheme of Example 1. Copolymer isolation andpurification/drying were conducted as described in Example 1. Fivetypical polymers (PII-F-1 to PII-F-4 and PII-S-1) were prepared usingthe general protocol. Pertinent reaction polymerizationcharge/conditions and analytical data are outlined in Tables III and IV.

TABLE III Synthesis and Properties of Type PII Fast-AbsorbingAmphiphilic Polyether-esters (PII-F-1 to PII-F-4) Composition of ChargeDSC Data Polymer PEG PEG/ Monomer Types Catalyst T_(m), ΔH_(f), NumberM_(n), kDa Polyester, (wt) & molar ratios^(a) M/C^(b) I.V.^(c) ° C. J/gPII-F-1 35 20/80 70/30 G/CL 10000 1.32 58, 125, 219 15, 9, 44 PII-F-2 3518/82 70/30 G/CL 8000 1.62 52, 128, 214 11, 6, 42 PII-F-3 20 10/90 90/10G/TMC 8000 1.66 221 77 PII-F-4 20  7/93 90/10 G/TMC 12000 1.51 230 72^(a)G = Glycolide; CL = ε-caprolactone; TMC = trimethylenecarbonate.^(b)Molar ratio of monomer to stannous octanoate. ^(c)Inherent viscosityin HFIP

TABLE IV Synthesis and Properties of Type PII Slow-Absorbing AmphiphilicPolyether-ester (PII-S-1) Composition of Charge DSC Data Polymer PEGPEG/ Monomer Types Catalyst T_(m), ΔH_(f), Number M_(n), kDa Polyester,(wt) & molar ratios^(a) M/C^(b) I.V.^(c) ° C. J/g PII-S-1 35 37/63 97/3LL/TMC 2000 86.9 147.1 0.86 ^(a)LL = l-lactide; TMC = trimethylenecarbonate; CL = ε-caprolactone. ^(b)Molar ratio of monomer to stannousoctanoate. ^(c)Gel permeation chromatography in CH₂Cl₂. ^(d)Inherentviscosity in CHCl₃

EXAMPLE 3 General Experimental Methods for Monofilament Spinning,Orientation, and In Vitro Testing

For Melt Spinning—A ¾″ single screw extruder is used. For a typicalslow-absorbing copolymer, having a maximum Tm of about 150, thetemperature profile used at the different zones of the extruder vary asfollows: Zone 1, 125° C.; Zone 2, 149° C.; Zone 3, 175° C.; andSpinhead, 185° C.

For Orientation'The temperature and draw conditions noted in Section 5.1will be applied using heated Godets.

For testing the properties of oriented monofilaments and then swellingbehavior, (1) the initial tensile properties, breaking strengthretention data of the monofilament sutures are determined using aMiniBionix MTS Universal Tester, Model 858; (2) the simulatedbioswelling properties are evaluated using an optical micrometer on thesample incubated in a phosphate buffer at 37° C. and pH 7.2; and (3) thein vitro BSR data were determined on sutures incubated in a phosphatebuffer at 37° C. and pH 7.2.

Polyether-esters PI-F-3, PI-F-4, PII-F-1, and PII-F-2 were converted tooriented monofilaments MI-F-3, MI-G-4, MII-F-1, and MII-F2 andpolyether-esters PI-S-1, PI-S-5, PI-S-6, PI-S-7, PI-S-8, PI-S-9, andPII-S-1 were converted to oriented monofilaments MI-S-1, MI-S-5, MI-S-6,MI-S-7, MI-S-8, MI-S-9, and MII-S-1 and tested for their in vitroproperties using the experimental procedures outlined above. Pertinenttensile properties, in vitro breaking strength retention (BSR), andswelling data are summarized in Tables V and VI.

TABLE V Extrusion of Polyether-esters PI-F-3, PI-F-4, PII-F-1, andPII-F-2 and Properties of Their Monofilaments as Sutures MonofilamentNumber Properties MI-F-3 MI-F-4 MII-F-1 MII-F-2 Copolymer used fromTable I PI-F-3 PI-F-4 PII-F-1 PII-F-2 Tensile properties Diameter, mm0.37 0.43 0.40    0.43 Linear strength, Kpsi (N) 60.7 (44.4) 30.7 (30.0)45.5 (46.3) 51.8 (51.9) Modulus, Kpsi 685 364 430 172  Elongation, % 3838 28 53 Knot strength, N 28.1 28.1 23.5   31.9 BSR^(a), % @ Days 3, 7,14, 21 — — — — Cross-sectional increase, % at 10 min. — — — — 60 min. —— —   20^(a) 16 hrs. — — — — ^(a)Using phosphate buffer at pH 7.2 and37° C.

TABLE VI Extrusion of Polyether-esters PI-S-1, PI-S-5, PI-S-6, PI-S-7,PI-S-8, PI-S-9, and PII-S-1 and Properties of Their Monofilaments asSutures Monofilament Number Properties MI-S-1 MI-S-5 MI-S-6 MI-S-7MI-S-8 MI-S-9 MII-S-1 Copolymer used from Table II PI-S-1 PI-S-5 PI-S-6PI-S-7 PI-S-8 PI-S-9 PII-S-1 Tensile properties Diameter, mm    0.130.22    0.23 0.36    0.47    0.29    0.10 Linear strength, Kpsi (N)  45.9 46.3   47.7 32.9   46.1   46.2   34.5   (4.2) (12.13)   (15.9)(23.5)   (55.6)   (20.7)    (1.87) Modulus, Kpsi 239  376 453  397 315 345  190  Elongation, % 44 73 73 57 90 91 99 Knot strength, N    2.6412.3   16.3 23.4   47.6   17.3 — BSR^(a), % @ Days 3, 7, 86, 72, 83, 65,— — — —, 63, — 14, 21 54, 41 47, 37 48, 39 Cross-sectional increase, 10min. — — — — — —  37^(b) % at 60 min. — —  57^(a) —   4^(a)  28^(a) 74^(b) 16 hrs.  72^(a) — — — — — — ^(a)Using phosphate buffer at pH 7.2and 37° C. ^(b)Using isotonic saline at 25° C.

EXAMPLE 4 Conversion of Polyether-Ester PI-S-6 to Monofilament Suturesand Evaluation of Their Properties

Detailed extrusion and orientation conditions of PI-S-6 (from Example 1,Table II), and tensile properties of oriented monofilaments aresummarized in Table VII.

TABLE VII Extrusion of Polyester-ester PI-S-6 and Properties of ItsMonofilament Temperature Profile During Extrusion, ° C. OrientationScheme Zone 1 Zone 2 Zone 3 Spinhead Draw Ratio/Temp, ° C. Polymer 120145 178 183 9-17/75-90 T_(m) = 172° C. Diameter Linear Max LinearStrength Modulus Elongation Knot Max (mm) Load (N) (kpsi) (kpsi) (%)Load (N) 0.28 17 35 314 94 16 0.24 16 43 400 65 15

Although the present invention has been described in connection with thepreferred embodiments, it is to be understood that modifications andvariations may be utilized without departing from the principles andscope of the invention, as those skilled in the art will readilyunderstand. Accordingly, such modifications may be practiced within thescope of the following claims. Moreover, Applicants hereby disclose allsubranges of all ranges disclosed herein. These subranges are alsouseful in carrying out the present invention.

EXAMPLE 5

General Experimental Methods for Multifilament Spinning, Orientation,Braiding, and Tensile Testing

The individual polymers were melt-spun into multifilament yarn using amulti-hold die, under slightly higher thermal conditions as compared tothose used in the production of the monofilaments in Example 4.Depending on the required yarn denier, the extruded multifilament yarnswere oriented in two stages at a temperature range of 60° C. to 85° C.Polyether-esters PII-F-3 and PII-F-4 were converted to braidedmultifilaments, and tested for their tensile properties using aMiniBionix MTS Universal Tester, Model 858. Braided multifilaments ofpolyether-esters PII-F-3 and PII-F-4, with diameters of 0.27 and 0.40 mmrespectively, exhibited tensile strengths of 61.2 and 40.0 Kpsi andelongations of 34% and 52% respectively.

Although the present invention has been described in connection with thepreferred embodiments, it is to be understood that modifications andvariations may be utilized without departing from the principles andscope of the invention, as those skilled in the art will readilyunderstand. Accordingly, such modifications may be practiced within thescope of the following claims. Moreover, Applicants hereby disclose allsubranges of all ranges disclosed herein. These subranges are alsouseful in carrying out the present invention.

1. A bioswellable suture comprising a compliant monofilament comprisingan absorbable polyether-ester, the monofilament having a tensile modulusof less than about 400 Kpsi and exhibiting an at least 20 percentincrease in cross-sectional area and an at least 5 percent decrease intensile modulus when placed in a biological environment.
 2. Abioswellable suture as in claim 1 wherein the polyether-ester comprisesa polyether glycol end-grafted with at least one cyclic monomer selectedfrom the group consisting of l-lactide, glycolide, p-dioxanone,trimethylene carbonate, ε-caprolactone, 1,5-dioxepan-2-one and amorpholinedione.
 3. A bioswellable suture as in claim 2 wherein thepolyether glycol is selected from the group consisting of polyethyleneglycol, polypropylene glycol, and block copolymers of ethylene glycoland propylene glycol.
 4. A bioswellable suture as in claim 3 wherein thepolyether glycol is a solid polyethylene glycol having a molecularweight of greater than about 8 kDa.
 5. A bioswellable suture as in claim4 wherein the polyethylene glycol comprises at least about 10 weightpercent of the total polyether-ester mass.
 6. A bioswellable suture asin claim 5 further comprising a surface coating on the monofilament,wherein the surface coating comprises at least about 0.01 weight percentof total mass of the suture.
 7. A bioswellable suture as in claim 6wherein the surface coating comprises an ε-caprolactone copolymer.
 8. Abioswellable suture as in claim 7 wherein the surface coating containsat least one bioactive agent selected from the group consisting ofantimicrobial agents, anti-inflammatory agents, and antineoplasticagents, the coated monofilament being capable of retaining at leastabout 40 percent of its initial breaking strength after placing in thebiological environment for four days.
 9. A bioswellable suturecomprising a compliant monofilament comprising a core layer and an outerlayer molecularly integrated with the core layer, the outer layercomprising highly hydrophilic moieties derived from grafts of at leastone unsaturated monomer selected from the group consisting ofhydroxyethyl methacrylate, maleic anhydride, itaconic anhydride, andmethacrylic acid, the monofilament having a tensile modulus of less thanabout 400 Kpsi and exhibiting an at least 20 percent increase incross-sectional area and an at least 5 percent decrease in tensilemodulus when placed in a biological environment.
 10. A bioswellablesuture as in claim 9 wherein the core layer comprises isotacticpolypropylene
 11. A bioswellable suture as in claim 9 wherein the corelayer comprises a non-absorbable segmented copolyester comprisingpolytetramethylene terephthalate.
 12. A bioswellable suture as in claim9 wherein the core layer comprises an aliphatic polyamide.
 13. Abioswellable suture as in claim 12 wherein the outer layer comprises apolyethylene oxide graft.
 14. A bioswellable suture as in claim 1comprising a braided non-absorbable multifilament encased in amolecularly integrated, highly swellable sheath.
 15. A bioswellablesuture as in claim 14 wherein the sheath comprises highly hydrophilicmoieties derived from grafts of at least one monomer selected from thegroup consisting of hydroxyethyl methacrylate, maleic anhydride,itaconic anhydride, and methacrylic acid, itaconic anhydride.
 16. Abioswellable suture as in claim 9 wherein the outer layer contains atleast one bioactive agent selected from the group consisting ofanti-inflammatory agents, antimicrobial agents, and antineoplasticagents.
 17. A bioswellable suture comprising an absorbable monofilamentcore and a non-absorbable multifilament braided sheath, the corecomprising polyethylene glycol end-grafted with at least one monomerselected from the group consisting of l-lactide, glycolide, trimethylenecarbonate, p-dioxanone, 1,5-dioxepan-2-one, ε-caprolactone, and amorpholinedione, the sheath comprising a heterochain polymer selectedfrom the group consisting of Nylon 6, Nylon 66, polyethyleneterephthalate, polybutylene terephthalate, polytrimethyleneterephthalate, segmented copolymers of polyallcylene terephthalate andpolytetramethylene glycol.
 18. A bioswellable suture as in claim 17further comprising a surface coating comprising aε-caprolactone/glycolide copolymer.
 19. A bioswellable suture as inclaim 17 comprising a surface coating comprising polyethylene glycolend-grafted with a mixture of ε-caprolactone and glycolide. 20-22.(canceled)